Effects of single and dual hypocretin-receptor blockade or knockdown of hypocretin projections to the central amygdala on alcohol drinking in dependent male rats

Gabriel M. Aldridge; Tyler A. Zarin; Adam J. Brandner; Olivier George; Nicholas W. Gilpin; Vez Repunte-Canonigo; Pietro Paolo Sanna; George F. Koob; Leandro F. Vendruscolo; Brooke E. Schmeichel

Addiction Neuroscience (Sep 2022)

Effects of single and dual hypocretin-receptor blockade or knockdown of hypocretin projections to the central amygdala on alcohol drinking in dependent male rats

Gabriel M. Aldridge,
Tyler A. Zarin,
Adam J. Brandner,
Olivier George,
Nicholas W. Gilpin,
Vez Repunte-Canonigo,
Pietro Paolo Sanna,
George F. Koob,
Leandro F. Vendruscolo,
Brooke E. Schmeichel

Affiliations

Gabriel M. Aldridge: Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, United States
Tyler A. Zarin: Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, United States
Adam J. Brandner: Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, United States
Olivier George: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, United States; Department of Psychiatry, School of Medicine, University of California, San Diego, CA 92093, United States
Nicholas W. Gilpin: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, United States; Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, United States
Vez Repunte-Canonigo: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, United States
Pietro Paolo Sanna: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, United States
George F. Koob: Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, United States; Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, United States
Leandro F. Vendruscolo: Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, United States; Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, United States
Brooke E. Schmeichel: Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, United States; Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, United States; Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, United States; Corresponding author.

Journal volume & issue: Vol. 3
p. 100028

Abstract

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Hypocretin/orexin (HCRT) is a neuropeptide that is associated with both stress and reward systems in humans and rodents. The different contributions of signaling at hypocretin-receptor 1 (HCRT-R1) and hypocretin-receptor 2 (HCRT-R2) to compulsive alcohol drinking are not yet fully understood. Thus, the current studies used pharmacological and viral-mediated targeting of HCRT to determine participation in compulsive alcohol drinking and measured HCRT-receptor mRNA expression in the extended amygdala of both alcohol-dependent and non-dependent male rats. Rats were made dependent through chronic intermittent exposure to alcohol vapor and were tested for the acute effect of HCRT-R1-selective (SB-408124; SB-R1), HCRT-R2-selective (NBI-80713; NB-R2), or dual HCRT-R1/2 (NBI-87571; NB-R1/2) antagonism on alcohol intake. NB-R2 and NB-R1/2 antagonists each dose-dependently decreased overall alcohol drinking in alcohol-dependent rats, whereas, SB-R1 decreased alcohol drinking in both alcohol-dependent and non-dependent rats at the highest dose (30 mg/kg). SB-R1, NB-R2, and NB-R1/2 treatment did not significantly affect water drinking in either alcohol-dependent or non-dependent rats. Additional PCR analyses revealed a significant decrease in Hcrtr1 mRNA expression within the central amygdala (CeA) of dependent rats under acute withdrawal conditions compared to non-dependent rats. Lastly, a shRNA-encoding adeno-associated viral vector with retrograde function was used to knockdown HCRT in CeA-projecting neurons from the lateral hypothalamus (LH). LH-CeA HCRT knockdown significantly attenuated alcohol self-administration in alcohol-dependent rats. These observations suggest that HCRT signaling in the CeA is necessary for alcohol-seeking behavior during dependence. Together, these data highlight a role for both HCRT-R1 and -R2 in dependent alcohol-seeking behavior.

Published in Addiction Neuroscience

ISSN: 2772-3925 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/addiction-neuroscience

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